PROJECT SUMMARY/ABSTRACT Patients with rheumatoid arthritis (RA) continue to experience a 30-40% excess mortality risk despite advances in disease management in the past two decades. During prior grant years, we established that cardiovascular (CV) disease is the leading cause of death in RA, and CV disease is increased 1.5-2 fold in patients with RA compared to the general population. We and others have shown that the excess CV mortality in RA has declined recently, but overall excess mortality in RA has not improved. We hypothesize that efforts to improve overall survival in RA by reducing CV death have failed because the systemic inflammation in RA affects multiple body systems, and the majority of patients exhibit complex health problems involving multiple, interrelated chronic health conditions (multimorbidity). In recent years the proportion of RA patients with multimorbidity and the mean number of morbidities per patient have increased. The goal of this application is to determine the complex interrelation between multimorbidity, RA disease activity, RA therapies, lifestyle, and other risk factors, and their impact on outcomes in patients with RA. The aims of this project are to: (1) determine multimorbidity clusters among persons with RA compared to similar persons without RA; (2) determine the impact of multimorbidity on long-term outcomes; and (3) develop and validate risk scores for common morbidities in RA. These aims will be accomplished utilizing the Rochester Epidemiology Project to expand (to n=2,295) and extend the existing population-based cohort of persons with RA, and utilizing a cohort of persons with RA (n>50,000) in the OptumLabs Data Warehouse. Multimorbidity clusters will be determined for persons with RA of different ages, sexes, races/ethnicities and geographic regions of the US. Longitudinal multimorbidity trajectories will be identified and their impact on outcomes among persons with RA will be compared to similar persons without RA. The impact of multimorbidity on mortality, physical functioning (determined by yearly assessments gathered over 20 years), healthcare utilization (outpatient visits, hospitalizations, emergency room visits and preventive services), and achievement of remission in RA will also be determined. New morbidity risk scores will be developed for cardiovascular disease, interstitial lung disease, and gastrointestinal bleeds/perforations. These and the existing scores for osteoporotic fractures and serious infections will be externally validated using the OptumLabs Data Warehouse. This information will determine how to identify persons with RA at the greatest risk for accumulating multimorbidity and how multimorbidity contributes to poor outcomes among persons with RA. Our findings will also stimulate the development of preventive strategies to delay the onset of multimorbidity (e.g., prevention of serious infections), which would slow the progression of multimorbidity and age-related declines in physical functioning and ultimately extend the lifespans of persons with RA.